There is disclosed in WO 96/11911 a class of novel compounds active as inhibitors of the activity of the 5-lipoxygenase enzyme, characterized by the following structural Formula (1.1.0): ##STR3##
wherein:
Ar.sup.1 is a heterocyclic moiety selected from the group consisting of imidazolyl; pyrrolyl; pyrazolyl; 1,2,3-triazolyl; 1,2,4-triazolyl; indolyl; indazolyl; and benzimidazolyl; bonded to X.sup.1 through a ring nitrogen atom; and substituted with 0-2 substituents selected from the group consisting of halo; hydroxy; cyano; amino; (C.sub.1 -C.sub.4)alkyl; (C.sub.1 -C.sub.4)alkoxy; (C.sub.1 -C.sub.4)alkylthio; (C.sub.1 -C.sub.4)halo-substituted alkyl; (C.sub.1 -C.sub.4)halo-substituted alkoxy; (C.sub.1 -C.sub.4)alkylamino; and di(C.sub.1 -C.sub.4)alkylamino;
X.sup.1 is a direct bond or (C.sub.1 -C.sub.4)alkylene;
Ar.sup.2 is phenylene substituted with 0-2 substituents selected from the group consisting of halo; hydroxy; cyano; amino; (C.sub.1-C.sub.4)alkyl; (C.sub.1 -C.sub.4)alkoxy; (C.sub.1 -C.sub.4)alkylthio; (C.sub.1 -C.sub.4)halo-substituted alkyl; and (C.sub.1 -C.sub.4)halo-substituted alkoxy;
X.sup.2 is --A-X-- or --X-A-- wherein A is a direct bond or (C.sub.1 -C.sub.4)alkylene and X is oxy; thio; sulfinyl; or sulfonyl;
Ar.sup.3 is a member selected from the group consisting of phenylene; pyridylene; thienylene; furylene; oxazolylene; and thiazolylene; substituted with 0-2 substituents selected from halo; hydroxy; cyano; amino; (C.sub.1 -C.sub.4)alkyl; (C.sub.1 -C.sub.4)alkoxy; (C.sub.1 -C.sub.4)alkylthio; (C.sub.1 -C.sub.4)halo-substituted alkyl; (C.sub.1 -C.sub.4)halo-substituted alkoxy; (C.sub.1 -C.sub.4)alkylamino; and di(C.sub.1 -C.sub.4)alkylamino;
R.sup.1 and R.sup.2 are each (C.sub.1 -C.sub.4)alkyl; or together they form a group of formula: --D.sup.1 -Z-D.sup.2 -- which together with the carbon atom to which it is attached defines a ring having 3 to 8 atoms, wherein D.sup.1 and D.sup.2 are (C.sub.1 -C.sub.4)alkylene and Z is a direct bond or oxy; thio; sulfinyl; sulfonyl; or vinylene; and D.sup.1 and D.sup.2 may be substituted by (C.sub.1 -C.sub.3)alkyl; and
Y is CONR.sup.3 R.sup.4 ; CN; C(R.sup.3).dbd.N-OR.sup.4 ; COOR.sup.3 ; COR.sup.3 ; or CSNR.sup.3 R.sup.4 ; wherein
R.sup.3 and R.sup.4 are each H or (C.sub.1 -C.sub.4)alkyl.
With respect to the above-recited compounds, the preferred meaning for (C.sub.1 -C.sub.4)halo-substituted alkyl is trifluoromethyl; and the preferred meaning for (C.sub.1 -C.sub.4)halo-substituted alkoxy is trifluoromethoxy. A preferred group of the above-recited compounds consists of those wherein Ar.sup.2 is 1,4-phenylene and Ar.sup.3 is 1,3-phenylene or 5-fluoro-1,3-phenylene. Within said preferred group, more preferred compounds are those in which Ar.sup.1 is 2-alkylimidazolyl; X.sup.1 is a direct bond; and Y is CONH.sup.2 ; and those in which Ar.sup.1 is pyrrolyl; X.sup.1 is CH.sub.2 ; and Y is CONH.sup.2.
A particularly preferred embodiment of the above-described class of inhibitory compounds is the following compound of Formula (1.0.0): ##STR4##
Compounds which inhibit the action of lipoxygenase enzyme are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals including humans. Lipoxygenase enzyme activity occurs as part of the arachidonic acid cascade. Arachidonic acid is the biological precursor of several groups of biologically active endogenous metabolites. Arachidonic acid is first released from membrane phospholipids via the action of phospholipase A2. Arachidonic acid is then metabolized (i) by cyclooxygenase to give prostaglandins including prostacyclin, and thromboxanes; or (ii) by lipoxygenase to give hydroperoxy fatty acids, which may be further converted to leukotrienes.
Leukotrienes, in turn, are extremely potent and elicit a wide variety of biological effects, e.g., peptidoleukotrienes, LTC.sub.4, LTD.sub.4, and LTE.sub.4, are important bronchoconstrictors and vaso-constrictors, and cause plasma extravasation by increasing capillary permeability. LTB.sub.4 is a potent chemotactic agent which intensifies leukocyte infiltration and degranulation at a site of inflammation. Leukotrienes have been implicated in a number of human disease states including asthma, chronic obstructive pulmonary disease, allergic rhinitis, rheumatoid arthritis, gout, psoriasis, atopic dermatitis, adult respiratory distress syndrome (ARDS), and inflammatory bowel diseases including. Crohn's disease. An agent which actively inhibits lipoxygenases, and as a consequence the production of leukotrienes, will be of significant therapeutic value in treating acute and chronic inflammatory conditions. See Masamune and Melvin, Annual Reports in Medicinal Chemistry 24, 71-80 (1989). Particular lipoxygenase inhibitors have been disclosed in EP 0 462 830; EP 0 505 122; and EP 0 540 165.
Several preparation processes for the lipoxygenase inhibitors described in above-mentioned published application WO 96/39408 are set forth therein. An example of such a preparation process is the coupling of a compound of Formula (1.2.0) and a compound of Formula (1.2.1), which may be represented by the reaction scheme set out below: ##STR5##
where Ar.sup.1 is 2-methyl-imidazol-1-yl; X.sup.1 is a direct bond; Ar.sup.2 and Ar.sup.3 are both phenylene; Y is CN; and R.sup.1 and R.sup.2 are taken together to form 3,4,5,6-tetrahydro-2H-pyran. X.sup.2 is S, resulting in a thioether, and is formed by the reaction of the two Q displaceable groups, in the presence of thiourea and a suitable catalyst, e.g., tetrakis(triphenylphosphine)-palladium, and a reducing agent, e.g., sodium cyanoborohydride. Reference is made to Chem. Lett., 1379-1380 (1986); and U.S. Pat. No. 5,883,106 mentioned further above. Suitable displaceable groups Q are said to include a halo or sulfonyloxy group.